SUMMARY: RGS14 is a multifunctional signaling protein that integrates G protein, MAPkinase, and calcium/CaM signaling pathways. RGS14 is found in brain where it is highly enriched in dendrites and spines of pyramidal neurons in hippocampal region CA2. We discovered that RGS14 is critically important as a natural suppressor of synaptic plasticity (long-term potentiation, LTP) in CA2 neurons. Our studies show that ectopic delivery of RGS14 to CA1 neurons where RGS14 is not expressed blocks LTP there, suggesting that RGS14 engages common signaling pathways that are critical for synaptic plasticity in both populations of neurons. Unlike CA1 neurons, little is known about CA2 neurons where RGS14 is expressed. This enigmatic brain region has been implicated in social behavior and human neuro-psychological diseases including schizophrenia, the autism/bipolar disorders, and epilepsy. Remarkably, we have found that mice lacking RGS14 (RGS14-KO) exhibit an unexpected enhancement of spatial learning and object recognition memory compared with wild type littermates, with no differences in non-hippocampal-dependent behaviors. Furthermore, RGS14-KO mice expressed a surprisingly robust nascent LTP with enhanced neuronal excitability at glutamatergic synapses in CA2, with no impact on plasticity in adjacent CA1 neurons. Together, these findings highlight the importance of understanding the molecular mechanism(s) whereby RGS14 regulates LTP and synaptic plasticity within CA2 hippocampal neurons. LTP and associated spine plasticity depends on a rise in postsynaptic calcium due to glutamate activation of NMDA/GluN channels and the voltage-gated calcium channel Cav1.2, which result in activation of CaM and CaMKII signaling pathways. These pathways, in turn, increase actomyosin-driven trafficking and insertion of AMPA/GluA receptor vesicles at the synapse that result in increased spine size (i.e. structural plasticity). Of note, we find that RGS14 suppresses the activity-induced rise in spine calcium, inhibits Cav1.2, binds Ca++/CaM, and is phosphorylated by CaMKII. Furthermore, we find that RGS14 suppresses spine structural plasticity associated with LTP, and exists in brain as part of a high-molecular weight complex enriched with spine myosins (MyoV, MyoVI, MyoII) and actin binding proteins. Based on these observations, our working hypothesis is that RGS14 suppresses spine calcium by inhibiting Cav1.2 channels, and blocks LTP by engaging the actomyosin system (in a regulated way) to limit surface AMPA receptors. We further propose that these actions of RGS14 are regulated by its binding partners CaM, CaMKII, H-Ras/Rap2-GTP and Gai1. To test these ideas, we propose the following experiments. AIM 1. Determine how Ca++/CaM binding and CaMKII phosphorylation modulate established RGS14 functions. AIM 2: Determine how RGS14 regulates Cav1.2 and suppresses postsynaptic calcium signaling in hippocampal neurons. AIM 3: Determine how RGS14 impacts AMPA receptor recycling and engages the actomyosin system to suppress spine plasticity in hippocampal neurons.